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Maija Huttunen-Lenz,1 Sylvia Hansen,1 Pia Christensen,2 Thomas Meinert Larsen,2 Finn Sandø-Pedersen,2 Mathijs Drummen,3 Tanja C Adam,3 Ian A Macdonald,4,5 Moira A Taylor,5 J Alfredo Martinez,6–8 Santiago Navas-Carretero,6–8 Svetoslav Handjiev,9 Sally D Poppitt,10 Marta P Silvestre,10 Mikael Fogelholm,11 Kirsi H Pietiläinen,12,13 Jennie Brand-Miller,14 Agnes AM Berendsen,15 Anne Raben,2 Wolfgang Schlicht1 1Department of Exercise and Health Sciences, University of Stuttgart, Stuttgart, Germany; 2Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark; 3Department of Nutrition and Movement Sciences, Maastricht University, Maastricht, the Netherlands; 4MRC/ARUK Centre for Musculoskeletal Ageing Research, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, School of Life Sciences, University of Nottingham, Nottingham, UK; 5School of Life Sciences, University of Nottingham Medical School, Nottingham, UK; 6Center for Nutrition Research at the University of Navarra, Pamplona, Spain; 7Madrid Institute of Advanced Studies (IMDEA Food), Madrid, Spain; 8Biomedical Research Centre Network in Physiopathology of Obesity and Nutrition (CIBERobn), Carlos III Institute, Madrid, Spain; 9Department of Pharmacology and Toxicology, Medical University – Sofia, Sofia, Bulgaria; 10Human Nutrition Unit, School of Biological Sciences, University of Auckland, Auckland, New Zealand; 11Department of Food and Nutrition, University of Helsinki, Helsinki, Finland; 12Obesity Research Unit, Research Program Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland; 13Abdominal Center, Endocrinology, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland; 14Charles Perkins Centre and School of Life and Environmental Biosciences, University of Sydney, Camperdown, NSW, Australia; 15Division of Human Nutrition & Health, Wageningen University & Research, Wageningen, the Netherlands Purpose: Onset of type 2 diabetes (T2D) is often gradual and preceded by impaired glucose homeostasis. Lifestyle interventions including weight loss and physical activity may reduce the risk of developing T2D, but adherence to a lifestyle change is challenging. As part of an international T2D prevention trial (PREVIEW), a behavior change intervention supported participants in achieving a healthier diet and physically active lifestyle. Here, our aim was to explore the influence of this behavioral program (PREMIT) on social-cognitive variables during an 8-week weight loss phase. Methods: PREVIEW consisted of an initial weight loss, Phase I, followed by a weight-­maintenance, Phase II, for those achieving the 8-week weight loss target of ≥ 8% from initial bodyweight. Overweight and obese (BMI ≥25 kg/m2) individuals aged 25 to 70 years with confirmed pre-diabetes were enrolled. Uni- and multivariate statistical methods were deployed to explore differences in intentions, self-efficacy, and outcome expectancies between those who achieved the target weight loss (“achievers”) and those who did not (“non-achievers”). Results: At the beginning of Phase I, no significant differences in intentions, self-efficacy and outcome expectancies between “achievers” (1,857) and “non-achievers” (163) were found. “Non-achievers” tended to be younger, live with child/ren, and attended the PREMIT sessions less frequently. At the end of Phase I, “achievers” reported higher intentions (healthy eating χ2(1)=2.57; P

Aims: The study aimed to determine whether alcohol use during late adolescence contributes to the weight gain from adolescence to young adulthood or risk of obesity or waist circumference at young adulthood. [ABSTRACT FROM PUBLISHER]

Introduction: Healthcare professionals' perspectives are often overlooked in the evaluation of digital weight loss interventions. Thus, we examined how healthcare professionals perceive patient success in a one-year web-based weight management program, the Healthy Weight Coaching, aiming to identify key success factors and common challenges within the coaching process., Methods: Thematic analysis was conducted on ten semi-structured interviews with healthcare professionals from the Healthy Weight Coaching. Interviewees included individuals of both sexes, with an average age of 41 years, ranging from 10 months to 5 years of coaching experience, and treating 90 to 500 patients., Results: Three main themes emerged from the analysis: (1) Positive progress during the Healthy Weight Coaching, (2) Factors facilitating success, and (3) Barriers hindering progress. The coaches noted significant positive changes among patients, including increased self-compassion, reduced weight-related stress, and a shift toward holistic well-being. Improvements in eating habits, physical activity, and vegetable consumption were observed, along with reductions in binge eating behaviors. Personal factors such as internal motivation and engagement with the program were crucial for success. Additionally, aspects of the Healthy Weight Coaching program, such as its individualized and supportive environment, flexible coaching approach, and the pivotal role of coaches, were seen as facilitators of success. Patients valued being treated equally and acceptingly and fostering trust and collaboration. However, challenges such as burdensome life situations, limited resources, and inadequate support posed significant barriers to progress. Unrealistic goals and societal pressures were also observed to hinder successful weight management efforts., Conclusion: A comprehensive, individualized approach addressing resource limitations and societal norms can enhance long-term success in weight management programs like the Healthy Weight Coaching, ultimately promoting overall well-being., (© 2024. The Author(s).)

Mechanisms of abdominal obesity GWAS variants have remained largely unknown. To elucidate these mechanisms, we leveraged subcutaneous adipose tissue (SAT) single nucleus RNA-sequencing and genomics data. After discovering that heritability of abdominal obesity is enriched in adipocytes, we focused on a SAT unique adipocyte marker gene, the transcription factor TBX15, and its abdominal obesity-associated deleterious missense variant, rs10494217. The allele frequency of rs10494217 revealed a north-to-south decreasing gradient, with consistent significant F ST values observed for 25 different populations when compared to Finns, a population with a history of genetic isolation. Given the role of Tbx15 in mouse thermogenesis, the frequency may have increased as an adaptation to cold in Finns. Our selection analysis provided significant evidence of selection for the abdominal obesity risk allele T of rs10494217 in Finns, with a north-to-south decreasing trend in other populations, and demonstrated that latitude significantly predicts the allele frequency. We also discovered that the risk allele status significantly affects SAT adipocyte expression of multiple adipocyte marker genes in trans in two cohorts. Two of these trans genes have been connected to thermogenesis, supporting the thermogenic effect of the TBX15 missense variant as a possible cause of its selection. Adipose expression of one trans gene, a lncRNA, AC002066.1, was strongly associated with adipocyte size, implicating it in metabolically unhealthy adipocyte hypertrophy. In summary, the abdominal obesity variant rs10494217 was selected in Finns, and individuals with the risk allele have trans effects on adipocyte expression of genes relating to thermogenesis and adipocyte hypertrophy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Human subcutaneous adipose tissue (SAT) contains a diverse array of cell-types; however, the epigenomic landscape among the SAT cell-types has remained elusive. Our integrative analysis of single-cell resolution DNA methylation and chromatin conformation profiles (snm3C-seq), coupled with matching RNA expression (snRNA-seq), systematically cataloged the epigenomic, 3D topology, and transcriptomic dynamics across the SAT cell-types. We discovered that the SAT CG methylation (mCG) landscape is characterized by pronounced hyper-methylation in myeloid cells and hypo-methylation in adipocytes and adipose stem and progenitor cells (ASPCs), driving nearly half of the 705,063 detected differentially methylated regions (DMRs). In addition to the enriched cell-type-specific transcription factor binding motifs, we identified TET1 and DNMT3A as plausible candidates for regulating cell-type level mCG profiles. Furthermore, we observed that global mCG profiles closely correspond to SAT lineage, which is also reflected in cell-type-specific chromosome compartmentalization. Adipocytes, in particular, display significantly more short-range chromosomal interactions, facilitating the formation of complex local 3D genomic structures that regulate downstream transcriptomic activity, including those associated with adipogenesis. Finally, we discovered that variants in cell-type level DMRs and A compartments significantly predict and are enriched for variance explained in abdominal obesity. Together, our multimodal study characterizes human SAT epigenomic landscape at the cell-type resolution and links partitioned polygenic risk of abdominal obesity to SAT epigenome.

Background/objectives: Obesity impairs intestinal glucose uptake (GU) (intestinal uptake of circulating glucose from blood) and alters gut microbiome. Exercise improves intestinal insulin-stimulated GU and alters microbiome. Genetics influence the risk of obesity and gut microbiome. However, the role of genetics on the effects of exercise on intestinal GU and microbiome is unclear., Methods: Twelve monozygotic twin pairs discordant for BMI (age 40.4 ± 4.5 years, BMI heavier 36.7 ± 6.0, leaner 29.1 ± 5.7, 8 female pairs) performed a six-month-long training intervention. Small intestine and colonic insulin-stimulated GU was studied using [ 18 F]FDG-PET and microbiota from fecal samples with 16s rRNA., Results: Ten pairs completed the intervention. At baseline, heavier twins had lower small intestine and colonic GU ( p < 0.05). Response to exercise differed between twins ( p = 0.05), with leaner twins increasing colonic GU. Alpha and beta diversity did not differ at baseline. During the intervention, beta diversity changed significantly, most prominently at the mid-point ( p < 0.01). Beta diversity changes were only significant in the leaner twins when the twin groups were analyzed separately. Exercise was associated with changes at the phylum level, mainly at the mid-point (pFDR < 0.05); at the genus level, several microbes increased, such as Lactobacillus and Sellimonas (pFDR < 0.05). In type 1 analyses, many genera changes were associated with exercise, and fewer, such as Lactobacillus , were also associated with dietary sugar consumption ( p < 0.05)., Conclusions: Obesity impairs insulin-stimulated intestinal GU independent of genetics. Though both twin groups exhibited some microbiota changes, most changes in insulin-stimulated colon GU and microbiota were significant in the leaner twins.

Obesity is a major global health issue with various metabolic complications. Both bariatric surgery and dieting achieve weight loss and improve whole-body metabolism, but vary in their ability to maintain these improvements over time. Adipose tissue and skeletal muscle metabolism are crucial in weight regulation, and obesity is linked to mitochondrial dysfunction in both tissues. The impact of bariatric surgery versus dieting on adipose tissue and skeletal muscle mitochondrial metabolism remains to be elucidated. Understanding the molecular pathways that modulate tissue metabolism following weight loss holds potential for identifying novel therapeutic targets in obesity management. This narrative review summarizes current knowledge on mitochondrial metabolism following bariatric surgery and diet-induced weight loss in adipose tissue and skeletal muscle, and sheds light on their respective effects., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes., Methods: STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m 2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA 1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA 1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete., Findings: Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m 2 (6·9), waist circumference 120·1 cm (14·7), HbA 1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported., Interpretation: Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia., Funding: Novo Nordisk., Translation: For the Spanish translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AV, HAKM, and MQ are employees and shareholders of Novo Nordisk. BMM received a research grant from Novo Nordisk; received honoraria as a consultant or speaker for Eli Lilly, Amgen, Novo Nordisk, Pfizer, and Johnson & Johnson; and is a shareholder of Reset Health. DCWL received clinical trial funding from Amgen and Novo Nordisk, and honoraria as a consultant or speaker for Amgen, Bayer, Boehringer Ingelheim, CME at Sea, Canada Collaborative Research Network, Eli Lilly, Novartis, Novo Nordisk, Viatris, and Zealand Pharma. JMB is a member of speakers bureaus for Merck, Boehringer Ingelheim, and Novo Nordisk, and has received research grants from the Novo Nordisk Foundation. KHP received honoraria for attendance or talks at meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, and Novo Nordisk, and research funding from the Novo Nordisk Foundation. MC received research grants and honoraria as a speaker for and member of advisory boards, and support to attend meetings from Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. SDP received consulting fees from AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, Bayer, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events for AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, GSK, Janssen, Boehringer Ingelheim, Sanofi, Merck, Abbott, Dexcom, HLS, Bayer, and Pfizer; support for attending meetings or travel from AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, and Bayer; and participation on data safety monitoring boards or advisory boards for AstraZeneca, Bausch, Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Merck, Abbott, HLS Therapeutics, Sanofi, Dexcom, and Bayer., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Obesity is an important health concern that poses many public health challenges. Evidence-based treatment modalities, capable of cost-effectively reaching large patient groups are needed. In this paper, we present the design and methods of the updated national, 12-month, digital weight management program, the Healthy Weight Coaching (HWC). The major updates, as compared to the previous version, are related to the theoretical background of the obesity management and updated BMI cut-offs. The HWC is available, based on physicians' referrals, to adult Finnish citizens with BMI ≥30 kg/m 2 or ≥27 kg/m 2 with a comorbidity, who have a health-based need to lose weight. Rooted in the principles of behavioural therapy, the HWC focuses on teaching coping skills, guides to healthy self-reflection, and supports concrete lifestyle changes as part of healthy weight loss. The automated weekly training sessions, supplemented by 3-8 exercises, form the basis of the program. These sessions address topics such as diet, physical activity, stress management, and rest and recovery. Additionally, a personal coach is allocated to each patient to provide tailored support. At baseline, patients record their weight, height, and waist circumference, online, and complete questionnaires on lifestyle, diet, physical activity, sleep, psychological factors, and health. Thereafter weight recording is conducted at least every 4 weeks, while the questionnaires and measuring the weight circumference are repeated at 3, 6, 9, and 12 months. In addition, patients can make use of diaries and peer group chats for additional support. Data collected from the consenting patients will be used for research purposes with the weight change from baseline to 12 months as the main outcome in the real-life observational study. The study will provide invaluable insights into the application of digital modalities in the treatment of obesity.

Obesity and sedentarism are associated with increased liver and pancreatic fat content (LFC and PFC, respectively) as well as impaired organ metabolism. Exercise training is known to decrease organ ectopic fat but its effects on organ metabolism are unclear. Genetic background affects susceptibility to obesity and the response to training. We studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. We recruited 12 BMI-discordant monozygotic twin pairs (age 40.4, SD 4.5 years; BMI 32.9, SD 7.6, 8 female pairs). Ten pairs completed six months of training intervention. We measured hepatic insulin-stimulated glucose uptake using [ 18 F]FDG-PET and fat content using magnetic resonance spectroscopy before and after the intervention. At baseline LFC, PFC, gamma-glutamyl transferase (GT), and hepatic glucose uptake were significantly higher in the heavier twins compared to the leaner co-twins ( p = 0.018, p = 0.02 and p = 0.01, respectively). Response to training in liver glucose uptake and GT differed between the twins (Time*group p = 0.04 and p = 0.004, respectively). Liver glucose uptake tended to decrease, and GT decreased only in the heavier twins ( p = 0.032). In BMI-discordant twins, heavier twins showed higher LFC and PFC, which may underlie the observed increase in liver glucose uptake and GT. These alterations were mitigated by exercise. The small number of participants makes the results preliminary, and future research with a larger pool of participants is warranted.

Background: Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants., Findings: We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue., Interpretation: Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis., Funding: NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki., Competing Interests: Declaration of interests M.L. was funded by the Sigrid Jusélius Foundation during the last 36 months. The other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To investigate cross-sectional associations between loneliness and health, health behaviours, and perceptions in Finnish individuals with overweight or obesity (BMI ≥25 kg/m 2 )., Methods: We used baseline data from patients participating, in 2016-2022, in a real-life digital 12-month weight management program known as Healthy Weight Coaching. Patients completed several questionnaires such as those related to loneliness, healthcare resource utilization, physical activity, and life satisfaction. BMI was computed based on self-reported weight and height. In addition to investigating individual health variables, we studied the association between loneliness and factor-analysis-derived health and wellbeing clusters., Results: Data were available from 2000 individuals (16.7% men, median age 48 years, median BMI 39.2 kg/m 2 ). Altogether, 11.6%, 42.4%, and 46.0% reported feeling lonely, somewhat lonely, and not lonely, respectively. Feeling lonely was associated with higher BMI, greater healthcare resource utilization, lower life satisfaction, burdensomeness of life, more negative perceptions related to obesity and to the upcoming coaching, lower daytime energy, and reduced 20-min brisk walk results, a measure of functional capacity. Of the five factor-analysis-derived clusters, loneliness was adversely associated with "Life satisfaction" [lonely, 0.337 (0.270-0.421), p < 0.001; somewhat lonely, 0.545 (0.475-0.625), p < 0.001]. Moreover, loneliness associated with "Negative perceptions of obesity/daytime fatigue" [lonely, 4.627 (3.391-6.314), p < 0.001; somewhat lonely 2.021 (1.694-2.412), p < 0.001], and "Obesity/low physical activity" [lonely, 1.474 (1.105-1.966), p = 0.008; somewhat lonely, 1.220 (1.019-1.460), p = 0.030]., Conclusions: Loneliness had several untoward associations with health, health behaviours, and perceptions. Further research should explore the intricate relationship between obesity, loneliness, and physical and psychosocial health., Trial Registration: The trial is registered at clinicaltrials.cov (Clinical Trials Identifier NCT04019249)., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Metabolic syndrome (MetS) is associated with premature aging, but whether this association is driven by genetic or lifestyle factors remains unclear., Methods: Two independent discovery cohorts, consisting of twins and unrelated individuals, were examined (N = 268, aged 23-69 years). The findings were replicated in two cohorts from the same base population. One consisted of unrelated individuals (N = 1 564), and the other of twins (N = 293). Participants' epigenetic age, estimated using blood DNA methylation data, was determined using the epigenetic clocks GrimAge and DunedinPACE. The individual-level linear regression models for investigating the associations of MetS and its components with epigenetic aging were followed by within-twin-pair analyses using fixed-effects regression models to account for genetic factors., Results: In individual-level analyses, GrimAge age acceleration was higher among participants with MetS (N = 56) compared to participants without MetS (N = 212) (mean 2.078 [95% CI = 0.996,3.160] years vs. -0.549 [-1.053,-0.045] years, between-group p = 3.5E-5). Likewise, the DunedinPACE estimate was higher among the participants with MetS compared to the participants without MetS (1.032 [1.002,1.063] years/calendar year vs. 0.911 [0.896,0.927] years/calendar year, p = 4.8E-11). An adverse profile in terms of specific MetS components was associated with accelerated aging. However, adjustments for lifestyle attenuated these associations; nevertheless, for DunedinPACE, they remained statistically significant. The within-twin-pair analyses suggested that genetics explains these associations fully for GrimAge and partly for DunedinPACE. The replication analyses provided additional evidence that the association between MetS components and accelerated aging is independent of the lifestyle factors considered in this study, however, suggesting that genetics is a significant confounder in this association., Conclusions: The results of this study suggests that MetS is associated with accelerated epigenetic aging, independent of physical activity, smoking or alcohol consumption, and that the association may be explained by genetics., (© 2024. The Author(s).)

Background: Age and obesity are dominant risk factors for several common cardiometabolic disorders, and both are known to impair adipose tissue function. However, the underlying cellular and genetic factors linking aging and obesity on adipose tissue function have remained elusive. Adipose stem and precursor cells (ASPCs) are an understudied, yet crucial adipose cell type due to their deterministic adipocyte differentiation potential, which impacts the capacity to store fat in a metabolically healthy manner., Methods: We integrated subcutaneous adipose tissue (SAT) bulk (n=435) and large single-nucleus RNA sequencing (n=105) data with the UK Biobank (UKB) (n=391,701) data to study age-obesity interactions originating from ASPCs by performing cell-type decomposition, differential expression testing, cell-cell communication analyses, and construction of polygenic risk scores for body mass index (BMI)., Results: We found that the SAT ASPC proportions significantly decrease with age in an obesity-dependent way consistently in two independent cohorts, both showing that the age dependency of ASPC proportions is abolished by obesity. We further identified 76 genes (72 SAT ASPC marker genes and 4 transcription factors regulating ASPC marker genes) that are differentially expressed by age in SAT and functionally enriched for developmental processes and adipocyte differentiation (i.e., adipogenesis). The 76 age-perturbed ASPC genes include multiple negative regulators of adipogenesis, such as RORA, SMAD3, TWIST2, and ZNF521, form tight clusters of longitudinally co-expressed genes during human adipogenesis, and show age-based differences in cellular interactions between ASPCs and adipose cell types. Finally, our genetic data demonstrate that cis-regional variants of these genes interact with age as predictors of BMI in an obesity-dependent way in the large UKB, while no such gene-age interaction on BMI is observed with non-age-dependent ASPC marker genes, thus independently confirming our cellular ASPC results at the biobank level., Conclusions: Overall, we discover that obesity prematurely induces a decrease in ASPC proportions and identify 76 developmentally important ASPC genes that implicate altered negative regulation of fat cell differentiation as a mechanism for aging and directly link aging to obesity via significant cellular and genetic interactions., (© 2024. The Author(s).)

Background: Preterm survivors have increased risk for impaired cardiometabolic health. We assessed glucose regulation and cardiometabolic biomarkers in adult very low birth weight (VLBW, <1500 g) survivors, using siblings as controls., Methods: VLBW-participants were matched with term-born, same-sex siblings. At mean age 29.2 years (SD 3.9), 74 VLBW-adults and 70 siblings underwent a 2-h 75 g oral glucose tolerance test and blood tests for assessment of cardiometabolic biomarkers., Results: Of participants, 23 (31%) VLBW and 11 (16%) sibling-controls met World Health Organization criteria for impaired glucose regulation (OR adjusted for age and sex 2.5, 95% CI: 1.1 to 5.8). Adjusting for age and sex, VLBW-participants showed 9.2% higher 2-h glucose (95% CI: 0.4% to 18.8%) than their siblings. Also, fasting (13.4%, -0.3% to 29.0%) and 2-h free fatty acids (15.6%, -2.4% to 36.9%) were higher in VLBW-participants. These differences were statistically significant only after further adjusting for confounders. No statistically significant differences were found regarding other measured biomarkers, including insulin resistance, atherogenic lipid profiles or liver tests., Conclusions: VLBW-adults showed more impaired fatty acid metabolism and glucose regulation. Differences in cardiometabolic biomarkers were smaller than in previous non-sibling studies. This may partly be explained by shared familial, genetic, or environmental factors., Impact: At young adult age, odds for impaired glucose regulation were 3.4-fold in those born at very low birth weight, compared to same-sex term-born siblings. Taking into consideration possible unmeasured, shared familial confounders, we compared cardiometabolic markers in adults born preterm at very low birth weight with term-born siblings. Prematurity increased risk for impaired glucose regulation, unrelated to current participant characteristics, including body mass index. In contrast to previous studies, differences in insulin resistance were not apparent, suggesting that insulin resistance may partially be explained by factors shared between siblings. Also, common cardiometabolic biomarkers were similar within sibling pairs., (© 2023. The Author(s).)

Aim: High body weight is a protective factor against osteoporosis, but obesity also suppresses bone metabolism and whole-body insulin sensitivity. However, the impact of body weight and regular training on bone marrow (BM) glucose metabolism is unclear. We studied the effects of regular exercise training on bone and BM metabolism in monozygotic twin pairs discordant for body weight., Methods: We recruited 12 monozygotic twin pairs (mean ± SD age 40.4 ± 4.5 years; body mass index 32.9 ± 7.6, mean difference between co-twins 7.6 kg/m 2 ; eight female pairs). Ten pairs completed the 6-month long training intervention. We measured lumbar vertebral and femoral BM insulin-stimulated glucose uptake (GU) using 18 F-FDG positron emission tomography, lumbar spine bone mineral density and bone turnover markers., Results: At baseline, heavier co-twins had higher lumbar vertebral BM GU (p < .001) and lower bone turnover markers (all p < .01) compared with leaner co-twins but there was no significant difference in femoral BM GU, or bone mineral density. Training improved whole-body insulin sensitivity, aerobic capacity (both p < .05) and femoral BM GU (p = .008). The training response in lumbar vertebral BM GU was different between the groups (time × group, p = .02), as GU tended to decrease in heavier co-twins (p = .06) while there was no change in leaner co-twins., Conclusions: In this study, regular exercise training increases femoral BM GU regardless of weight and genetics. Interestingly, lumbar vertebral BM GU is higher in participants with higher body weight, and training counteracts this effect in heavier co-twins even without reduction in weight. These data suggest that BM metabolism is altered by physical activity., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity., (© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Communication between adipocytes and endothelial cells (EC) is suggested to play an important role in the metabolic function of white adipose tissue. In order to generate tools to investigate in detail the physiology and communication of EC and adipocytes, a method for isolation of adipose microvascular EC from visceral adipose tissue (VAT) biopsies of subjects with obesity was developed. Moreover, mature white adipocytes were isolated from the VAT biopsies by a method adapted from a previously published Membrane aggregate adipocytes culture (MAAC) protocol. The identity and functionality of the cultivated and isolated adipose microvascular EC (AMvEC) was validated by imaging their morphology, analyses of mRNA expression, fluorescence activated cell sorting (FACS), immunostaining, low-density lipoprotein (LDL) uptake, and in vitro angiogenesis assays. Finally, we established a new trans filter co-culture system (membrane aggregate adipocyte and endothelial co-culture, MAAECC) for the analysis of communication between the two cell types. EC-adipocyte communication in this system was validated by omics analyses, revealing several altered proteins belonging to pathways such as metabolism, intracellular transport and signal transduction in adipocytes co-cultured with AMvEC. In reverse experiments, induction of several pathways including endothelial development and functions was found in AMvEC co-cultured with adipocytes. In conclusion, we developed a robust method to isolate EC from small quantities of human VAT. Furthermore, the MAAECC system established during the study enables one to study the communication between primary white adipocytes and EC or vice-versa and could also be employed for drug screening., Competing Interests: Declaration of competing Interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: The relationship between obesity and mental health is complex and is moderated by the level of obesity, age, sex, and social and genetic factors. In the current study, we used a unique co-twin control design, with twin pairs discordant for body mass index (BMI), to control for shared genetic and environmental effects between obesity and several dimensions of mental health., Methods: We studied 74 monozygotic (MZ) twin pairs, of whom 36 were BMI-discordant (intra-pair difference in BMI ≥ 3 kg/m2), and 77 dizygotic (DZ) twin pairs (46 BMI-discordant). We assessed subjective health, especially mental health and mental well-being (depression, anxiety, self-esteem, health-related quality of life, life satisfaction, and social well-being) through questionnaires., Results: Heavier MZ co-twins from BMI-discordant pairs had poorer general health (58.8±3.0 vs. 72.4±3.8, P = 0.001, FDR = 0.017 on a scale from 0 to 100 where higher scores indicate more positive results), physical functioning (90.3±1.1 vs. 95.5±2.2, P = 0.024, FDR = 0.122), energy levels (55.6±3.4 vs. 66.6±3.3, P = 0.013, FDR = 0.109), and emotional well-being (65.9±3.2 vs. 75.4±2.9, P = 0.031, FDR = 0.122), as well as a tendency for depressive symptoms (8.4±1.3 vs. 5.6±0.9, P = 0.071, FDR = 0.166) compared to their leaner co-twins. Heavier DZ co-twins had poorer total physical well-being (91.6±1.9 vs. 95.6±1.0, P = 0.035, FDR = 0.356) and more depressive symptoms (4.3±0.9 vs. 2.4±0.5, P = 0.016, FDR = 0.345 on a scale from 0 to 63 where lower scores indicate fewer depressive symptoms) than their leaner co-twins. Association analyses, using all twin pairs, confirmed that higher BMI within pairs linked to general health, physical functioning and depressive symptoms. No association was found between BMI and anxiety, self-esteem, life satisfaction, or social well-being., Conclusions: In conclusion, this study underscores the notable association between elevated BMI and physical well-being and to a lesser extent between elevated BMI and depressive symptoms, while revealing no discernible connections with anxiety, self-esteem, life satisfaction, or social well-being., Competing Interests: The authors have declared no conflicts of interest., (Copyright: © 2023 Kupila et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: This study investigated 36-year BMI trajectories in twins whose BMI in young adulthood was below, within, or above their genetically predicted BMI, with a focus on twin pairs with large intrapair BMI differences (within-pair ΔBMI ≥ 3 kg/m 2 )., Methods: Together, 3227 like-sexed twin pairs (34% monozygotic) were examined at age ~30 years in 1975 and followed up in 1981, 1990, and 2011. An individual's observed BMI in 1975 was considered within (±2.0), below (<-2.0), or above (>+2.0) genetically predicted BMI, measured by a polygenic risk score of 996,919 single nucleotide polymorphisms., Results: In monozygotic and dizygotic twin pairs with large intrapair BMI differences, the co-twin with a higher observed BMI in 1975 deviated above predicted BMI more frequently (~2/3) than the co-twin with a lower BMI deviated below prediction (~1/3). Individuals below, within, and above prediction in 1975 reached, respectively, normal weight, overweight, and obesity by 2011, with a mean BMI increase of 4.5 (95% CI: 4.3-4.8)., Conclusions: Categorizing BMI as below, within, or above polygenic risk score-predicted BMI helps identifying individuals who have been resistant or susceptible to weight gain. This may provide new insights into determinants and consequences of obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Objective: Although it has been suggested that one-anastomosis gastric bypass (OAGB) is metabolically superior to the "gold standard," i.e., Roux-en-Y gastric bypass (RYGB), there is little robust evidence to prove it. Because this result may arise from the typically longer length of bypassed intestine in OAGB, here, the authors standardized the bypass length in RYGB and OAGB and compared weight loss and metabolic outcomes in a randomized controlled trial., Methods: The authors randomized 121 bariatric patients to RYGB (n = 61) or OAGB (n = 60) in two Finnish University Hospitals and measured weight; body composition; metabolic features (insulin sensitivity, lipids, inflammation, nutrition); and comorbidities before and 6 and 12 months after the operation., Results: Total weight loss was similar in RYGB and OAGB at 6 months (mean: 21.2% [95% CI: 19.4-23.0] vs. 22.8% [95% CI: 21.5-24.1], p = 0.136) and 12 months (25.4% [95% CI: 23.4-27.5] vs. 26.1% [95% CI: 24.2-28.9], p = 0.635). Insulin sensitivity, lipids, and inflammation improved similarly between the groups (p > 0.05). Remission of type 2 diabetes and hypercholesterolemia was marked and similar (p > 0.05) but the use of antihypertensive medications was lower (p = 0.037) and hypertension tended to improve more (p = 0.053) with RYGB versus OAGB at 12 months. Higher rates of vitamin D-25 deficiency (p < 0.05) and lower D-25 levels were observed with OAGB versus RYGB throughout the follow-up (p < 0.001). No differences in adverse effects were observed., Conclusions: RYGB and OAGB were comparable in weight loss, metabolic improvement, remission of diabetes and hypercholesterolemia, and nutrition at 1-year follow-up. Vitamin D-25 deficiency was more prevalent with OAGB, whereas reduction in antihypertensive medications and hypertension was greater with RYGB. There is no need to change the current practices of RYGB in favor of OAGB., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

This study aims to develop and validate a modeling framework to predict long-term weight change on the basis of self-reported weight data. The aim is to enable focusing resources of health systems on individuals that are at risk of not achieving their goals in weight loss interventions, which would help both health professionals and the individuals in weight loss management. The weight loss prediction models were built on 327 participants, aged 21-78, from a Finnish weight coaching cohort, with at least 9 months of self-reported follow-up weight data during weight loss intervention. With these data, we used six machine learning methods to predict weight loss after 9 months and selected the best performing models for implementation as modeling framework. We trained the models to predict either three classes of weight change (weight loss, insufficient weight loss, weight gain) or five classes (high/moderate/insufficient weight loss, high/low weight gain). Finally, the prediction accuracy was validated with an independent cohort of overweight UK adults (n = 184). Of the six tested modeling approaches, logistic regression performed the best. Most three-class prediction models achieved prediction accuracy of > 50% already with half a month of data and up to 97% with 8 months. The five-class prediction models achieved accuracies from 39% (0.5 months) to 89% (8 months). Our approach provides an accurate prediction method for long-term weight loss, with potential for easier and more efficient management of weight loss interventions in the future. A web application is available: https://elolab.shinyapps.io/WeightChangePredictor/ .The trial is registered at clinicaltrials.gov/ct2/show/NCT04019249 (Clinical Trials Identifier NCT04019249), first posted on 15/07/2019., (© 2023. The Author(s).)

Understanding differences in adipose gene expression between individuals with different levels of clinical traits may reveal the genes and mechanisms leading to cardiometabolic diseases. However, adipose is a heterogeneous tissue. To account for cell-type heterogeneity, we estimated cell-type proportions in 859 subcutaneous adipose tissue samples with bulk RNA sequencing (RNA-seq) using a reference single-nuclear RNA-seq data set. Cell-type proportions were associated with cardiometabolic traits; for example, higher macrophage and adipocyte proportions were associated with higher and lower BMI, respectively. We evaluated cell-type proportions and BMI as covariates in tests of association between >25,000 gene expression levels and 22 cardiometabolic traits. For >95% of genes, the optimal, or best-fit, models included BMI as a covariate, and for 79% of associations, the optimal models also included cell type. After adjusting for the optimal covariates, we identified 2,664 significant associations (P ≤ 2e-6) for 1,252 genes and 14 traits. Among genes proposed to affect cardiometabolic traits based on colocalized genome-wide association study and adipose expression quantitative trait locus signals, 25 showed a corresponding association between trait and gene expression levels. Overall, these results suggest the importance of modeling cell-type proportion when identifying gene expression associations with cardiometabolic traits., (© 2023 by the American Diabetes Association.)

Background: Adipocytes are crucial regulators of cardiovascular health. However, not much is known about gene expression profiles of adipocytes residing in nonfat cardiovascular tissues, their genetic regulation, and contribution to coronary artery disease. Here, we investigated whether and how the gene expression profiles of adipocytes in the subcutaneous adipose tissue differ from adipocytes residing in the heart., Methods: We used single-nucleus RNA-sequencing data sets of subcutaneous adipose tissue and heart and performed in-depth analysis of tissue-resident adipocytes and their cell-cell interactions., Results: We first discovered tissue-specific features of tissue-resident adipocytes, identified functional pathways involved in their tissue specificity, and found genes with cell type-specific expression enrichment in tissue-resident adipocytes. By following up these results, we discovered the propanoate metabolism pathway as a novel distinct characteristic of the heart-resident adipocytes and found a significant enrichment of coronary artery disease genome-wide association study risk variants among the right atrium-specific adipocyte marker genes. Our cell-cell communication analysis identified 22 specific heart adipocyte-associated ligand-receptor pairs and signaling pathways, including THBS (thrombospondin) and EPHA (ephrin type-A), further supporting the distinct tissue-resident role of heart adipocytes. Our results also suggest chamber-level coordination of heart adipocyte expression profiles as we observed a consistently larger number of adipocyte-associated ligand-receptor interactions and functional pathways in the atriums than ventricles., Conclusions: Overall, we introduce a new function and genetic link to coronary artery disease for the previously unexplored heart-resident adipocytes., Competing Interests: Disclosures None.

Cold-induced brown adipose tissue (BAT) activation is considered to improve metabolic health. In murine BAT, cold increases the fundamental molecule for mitochondrial function, nicotinamide adenine dinucleotide (NAD + ), but limited knowledge of NAD + metabolism during cold in human BAT metabolism exists. We show that cold increases the serum metabolites of the NAD + salvage pathway (nicotinamide and 1-methylnicotinamide) in humans. Additionally, individuals with cold-stimulated BAT activation have decreased levels of metabolites from the de novo NAD + biosynthesis pathway (tryptophan, kynurenine). Serum nicotinamide correlates positively with cold-stimulated BAT activation, whereas tryptophan and kynurenine correlate negatively. Furthermore, the expression of genes involved in NAD + biosynthesis in BAT is related to markers of metabolic health. Our data indicate that cold increases serum tryptophan conversion to nicotinamide to be further utilized by BAT. We conclude that NAD + metabolism is activated upon cold in humans and is probably regulated in a coordinated fashion by several tissues., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/objectives: Some individuals with overweight/obesity may be relatively metabolically healthy (MHO) and have a lower risk of cardiovascular disease than those with metabolically unhealthy overweight/obesity (MUO). We aimed to compare changes in body weight and cardiometabolic risk factors and type 2 diabetes incidence during a lifestyle intervention between individuals with MHO vs MUO., Methods: This post-hoc analysis included 1012 participants with MHO and 1153 participants with MUO at baseline in the randomized trial PREVIEW. Participants underwent an eight-week low-energy diet phase followed by a 148-week lifestyle-based weight-maintenance intervention. Adjusted linear mixed models and Cox proportional hazards regression models were used., Results: There were no statistically significant differences in weight loss (%) between participants with MHO vs MUO over 156 weeks. At the end of the study, weight loss was 2.7% (95% CI, 1.7%-3.6%) in participants with MHO and 3.0% (2.1%-4.0%) in those with MUO. After the low-energy diet phase, participants with MHO had smaller decreases in triglyceride (mean difference between MHO vs MUO 0.08 mmol·L -1 [95% CI, 0.04-0.12]; P < 0.001) but similar reductions in fasting glucose and HOMA-IR than those with MUO. However, at the end of weight maintenance, those with MHO had greater reductions in triglyceride (mean difference -0.08 mmol·L -1 [-0.12--0.04]; P < 0.001), fasting glucose, 2-hour glucose (difference -0.28 mmol·L -1 [-0.41--0.16]; P < 0.001), and HOMA-IR than those with MUO. Participants with MHO had smaller decreases in diastolic blood pressure and HbA 1c and greater decreases in HDL cholesterol after weight loss than those with MUO, whereas the statistically significant differences disappeared at the end of weight maintenance. Participants with MHO had lower 3-year type 2 diabetes incidence than those with MUO (adjusted hazard ratio 0.37 [0.20-0.66]; P < 0.001)., Conclusions: Individuals with MUO had greater improvements in some cardiometabolic risk factors during the low-energy diet phase, but had smaller improvements during long-term lifestyle intervention than those with MHO., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

PURPOSE OF REVIEW: The purpose of this study is to evaluate the effectiveness of eHealth interventions for weight loss and weight loss maintenance among adults with overweight or obesity through a systematic review of systematic reviews. RECENT FINDINGS: This study included 26 systematic reviews, covering a total of 338 original studies, published between 2018 and 2023. The review indicates that eHealth interventions are more effective than control interventions or no care and comparable to face-to-face interventions. The effect sizes remain relatively small when comparing eHealth interventions to any control conditions, with mean differences of weight loss results from - 0.12 kg (95% CI - 0.64 to 0.41 kg) in a review comparing eHealth interventions to face-to-face care to - 4.32 kg (- 5.08 kg to - 3.57 kg) in a review comparing eHealth interventions to no care. The methodological quality of the included studies varies considerably. However, it can be concluded that interventions with human contact work better than those that are fully automated. In conclusion, this systematic review of systematic reviews provides an updated understanding of the development of digital interventions in recent years and their effectiveness for weight loss and weight loss maintenance among adults with overweight or obesity. The findings suggest that eHealth interventions can be a valuable tool for delivering obesity care to more patients economically. Further research is needed to determine which specific types of eHealth interventions are most effective and how to best integrate them into clinical practice., (© 2023. The Author(s).)

Context: The neutral amino acid transporter SLC7A10/ASC-1 is an adipocyte-expressed gene with reduced expression in insulin resistance and obesity. Inhibition of SLC7A10 in adipocytes was shown to increase lipid accumulation despite decreasing insulin-stimulated uptake of glucose, a key substrate for de novo lipogenesis. These data imply that alternative lipogenic substrates to glucose fuel continued lipid accumulation during insulin resistance in obesity., Objective: We examined whether increased lipid accumulation during insulin resistance in adipocytes may involve alter flux of lipogenic amino acids dependent on SLC7A10 expression and activity, and whether this is reflected by extracellular and circulating concentrations of marker metabolites., Methods: In adipocyte cultures with impaired SLC7A10, we performed RNA sequencing and relevant functional assays. By targeted metabolite analyses (GC-MS/MS), flux of all amino acids and selected metabolites were measured in human and mouse adipose cultures. Additionally, SLC7A10 mRNA levels in human subcutaneous adipose tissue (SAT) were correlated to candidate metabolites and adiposity phenotypes in 2 independent cohorts., Results: SLC7A10 impairment altered expression of genes related to metabolic processes, including branched-chain amino acid (BCAA) catabolism, lipogenesis, and glyceroneogenesis. In 3T3-L1 adipocytes, SLC7A10 inhibition increased fatty acid uptake and cellular content of glycerol and cholesterol. SLC7A10 impairment in SAT cultures altered uptake of aspartate and glutamate, and increased net uptake of BCAAs, while increasing the net release of the valine catabolite 3- hydroxyisobutyrate (3-HIB). In human cohorts, SLC7A10 mRNA correlated inversely with total fat mass, circulating triacylglycerols, BCAAs, and 3-HIB., Conclusion: Reduced SLC7A10 activity strongly affects flux of BCAAs in adipocytes, which may fuel continued lipogenesis during insulin resistance, and be reflected in increased circulating levels of the valine-derived catabolite 3-HIB., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Obesity is a chronic, progressive and relapsing disease with a rising global prevalence associated with increased morbidity and mortality and reduced quality of life. Treatment of obesity requires a comprehensive medical approach that includes behavioural interventions, pharmacotherapy and bariatric surgery. The degree of weight loss with all approaches is highly heterogeneous, and long-term weight maintenance remains challenging. For years, antiobesity medications have been limited in number, often delivering meagre efficacy and raising numerous safety concerns. Therefore, there is a need for the development of highly efficacious and safe new agents. Recent insights into the complex pathophysiology of obesity have increased our understanding of intervenable targets for pharmacotherapies to treat obesity and improve weight-related cardiometabolic complications, namely, type 2 diabetes, hyperlipidaemia and hypertension. As a result, novel potent therapies have emerged, such as semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) recently approved for the treatment of obesity. Semaglutide 2.4 mg once weekly significantly reduces body weight by approximately 15%, with simultaneous improvement in cardiometabolic risk factors and physical functioning in people with obesity. Tirzepatide, the first dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RA, has recently demonstrated that body weight reduction exceeding 20% in people with obesity and coupled with improved cardiometabolic measures is feasible. Thus, these novel agents promise to narrow the gap between the weight-loss effects of behaviour interventions, previous pharmacotherapies, and bariatric surgery. In this narrative review, we highlight established and emerging therapeutic treatments for long-term obesity management and position them in a framework according to their weight loss effects., (© 2023 John Wiley & Sons Ltd.)

Obesity-induced adipose tissue dysfunction can cause low-grade inflammation and downstream obesity comorbidities. Although preadipocytes may contribute to this pro-inflammatory environment, the underlying mechanisms are unclear. We used human primary preadipocytes from body mass index (BMI) -discordant monozygotic (MZ) twin pairs to generate epigenetic (ATAC-sequence) and transcriptomic (RNA-sequence) data for testing whether increased BMI alters the subnuclear compartmentalization of open chromatin in the twins' preadipocytes, causing downstream inflammation. Here we show that the co-accessibility of open chromatin, i.e. compartmentalization of chromatin activity, is altered in the higher vs lower BMI MZ siblings for a large subset ( ~ 88.5 Mb) of the active subnuclear compartments. Using the UK Biobank we show that variants within these regions contribute to systemic inflammation through interactions with BMI on C-reactive protein. In summary, open chromatin co-accessibility in human preadipocytes is disrupted among the higher BMI siblings, suggesting a mechanism how obesity may lead to inflammation via gene-environment interactions., (© 2023. The Author(s).)

Aim: To characterize healthcare resource (HCRU) and medication use and associated costs in individuals with obesity compared with individuals with normal weight or overweight in a population-based cohort of Finnish adults. The association between metabolic state and direct costs was also assessed., Methods: The study cohort included 5587 randomly selected individuals who participated in the national FinHealth 2017 health examination survey. Data on healthcare visits and hospital stays, including diagnoses (ICD-10), and purchases and costs of prescription medicines were collected from the nationwide registers by the Finnish Institute for Health and Welfare and Social Insurance Institution of Finland. The healthcare costs were calculated based on standard unit costs reported by the Finnish Institute for Health and Welfare., Results: The total annual direct costs were €2665 (SD €5673) and €1799 (SD €3874) per person with obesity and with normal weight or overweight, respectively. Obesity was associated with significantly increased total direct (age- and sex-adjusted cost rate ratio, RR, 1.356; p < 0.001), HCRU-related (1.273; p = 0.002), and medication (1.669; p < 0.001) costs. A vast majority (90%) of individuals with obesity were classified as metabolically unhealthy based on clinical measurements. The metabolically unhealthy state was associated with increased costs in individuals with obesity but not in individuals with normal weight or overweight., Conclusion: Obesity is associated with a significant and complex direct cost burden to society, arising primarily from increased comorbidity. Metabolically healthy obesity is uncommon and obesity prevention and timely treatment should be of high priority to tackle the increasing burden of obesity., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver., Methods: To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals' subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis., Findings: We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels., Interpretation: Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease., Funding: The work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research., Competing Interests: Declaration of interests J. N. B. received consulting fees from GLG, and support for attending meetings and/or travel from the American Gastroenterology Association (AGA), at least once during the last 36 months. The other authors declare that they have no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Liraglutide (LG), a glucagon-like peptide-1 receptor (GLP-1R) agonist, has been shown to improve white adipose tissue mitochondrial metabolism in mice but not in human adipocytes. Therefore, we explored whether LG has therapeutic efficacy in mitochondrial dysfunction in human adipocytes in vitro., Methods: We tested the effects of short-term (ST-LG: 24 h) and long-term (LT-LG: D0-15 days) treatments in human SGBS adipocytes on mitochondrial respiration, mRNA and protein expression. GLP-1R inhibition was investigated by the co-treatment of GLP-1R inhibitor, exendin 9-39 (Ex9-39) and ST-LG treatment. We also explored the ability of ST-LG to alleviate mitochondrial dysfunction induced by tumor necrosis factor-alpha (TNFα)., Results: LT-LG treatment induced the formation of smaller lipid droplets and increased the expression of genes related to lipolysis. Both ST-LG and LT-LG treatments promoted mitochondrial respiration. Additionally, LT-LG treatment increased the expression of a brown adipocyte marker, uncoupling protein 1 (UCP-1), and the markers of mitochondrial biogenesis. Interestingly, ST-LG rescued TNFα-induced defects in mitochondrial energy metabolism and inflammation in SGBS adipocytes., Conclusion: LG stimulates mitochondrial respiration and biogenesis in human adipocytes, potentially via UCP-1-mediated adipocyte browning. Importantly, our study demonstrates for the first time that LG has a therapeutic potential on mitochondrial activity in human adipocytes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)